This invention relates to compositions containing a therapeutic component which is susceptible to oxidative degradation. More particularly, this invention relates to such compositions especially formulated for topical application in which the oxidation-prone therapeutic ingredient is a proteinaceous biological response modifier such as an interferon or other lymphokine.
Since their discovery in 1957, the interferons, a complex family of several species and multiple subspecies of hormone-like cellular proteins, have been widely investigated for their potent antiviral, antiproliferative and immunomodulating properties.
The major interferon species are now designated alpha, beta and gamma according to their origin and mode of induction. Leukocytes are the primary producers of the alpha species, fibroblasts mainly that of the beta species and T lymphocytes are the principal source of the gamma species. Collectively, the alpha and beta interferons are classified as Type I interferons, Type II being immune interferons. Each of these interferon species have been produced on an industrial scale employing recombinant techniques in bacteria and yeast with purification being accomplished by means of classical techniques or by monoclonal immunosorbent antibody. General discussions of these interferons can be found in various texts and monographs, including The Interferon System, by W. E. Stewart, II, Springer-Verlag, New York (1979); Interferon 1981, Vol. 3, edited by Ion Gresser, Academic Press, New York (1981); and Interferon Therapy, World Health Organization Technical Reports Series 676, World Health Organization, Geneva, 1982.
For over a decade, interferons of all types have been employed in clinical trials. Originally, they were applied against viral pathogens, but subsequently their use has been extended to include treatment of a variety of malignant diseases An important factor in the clinical application of interferons and other lymphokines is the method of administration. Systemic administration, by either intravenous of intramuscular injection, has been used most frequently with some success. Among the problems inherent in this method of administrations is that the interferon can come into contact with uninfected or nonmalignant cells causing unwanted side effects. Accordingly, the preferred approach would be to deliver interferon directly to the affected tissues or organs. In some cases, this can be accomplished by direct injection into the diseased site. In other cases, e.g., eye disease and diseases like herpes genitalis, herpes labialis, herpes zoster and adenovirus induced keratitis and condyloma, all of which produce skin lesions, local topical application is the preferred method of administration. The topical administration of interferon has proved to be a formidable problem for a number of reasons. First, interferon is a protein with a higher molecular weight than the molecular weights of therapeutic agents previously administered in topical preparations, e.g., procaine, nitroglycerin, etc. In general, large molecular weight proteins have a much smaller solution diffusion coefficient than low molecular weight substances, a difference which generally becomes exacerbated in semi-solid media. Accordingly, the vehicle used to administer interferon locally must be able to hold the high molecular weight interferon in suspension during packaging, shipping and application, and yet also be able to release the interferon from the vehicle in a reasonable length of time once it has been applied to the diseased site. Second, the vehicle must not adversely affect the activity of the interferon by direct chemical action, precipitation or immobilization, any of which would preclude interaction of the interferon with the diseased site.
Third, and in many ways the most difficult objective to achieve, the vehicle should allow the interferon preparation a sufficiently long shelf-life at room and body temperatures to allow for convenient shipping, handling and administration by the patient. In general terms, if a therapeutic agent is to be administered topically, the agent and its vehicle should satisfy the following shelf-life conditions: (1) the agent should retain a significant fraction of its therapeutic effect when held at room temperature (e.g., about 22.degree. C.) for a period of approximately fourteen days and (2) the agent should also retain a significant fraction of its activity when held at body temperature (37.degree. C.) for a period of approximately one day. The fourteen day requirement at room temperature allows for shipping, handling and retailing of the preparation. The one-day requirement at body temperature allows the patient to carry the product on his person and apply it throughout the day when needed.
Interferons produced by recombinant-DNA techniques or from natural sources when in a crude or partially purified form are notoriously temperature-labile substances.
For example, Moller, et al. reported at the Third Annual International Congress for Interferon Research that even at 4.degree. C., a human leukocyte interferon gel lost 80% of its activity in just two weeks. (Moller, B. R., Johannesen, P., Osther, K., Ulmsteen, U., Hastrup, J. and Berg, K., "Initial Evaluation of Topical Treatment of Dysplasia of the Cervical Epithelium with a Human Leukocyte Interferon Gel,", Third Annual International Congress for Interferon Research, 1982.) Plainly, this is far from the fourteen days at 22.degree. C. and one day at 37.degree. C. stability requirements which an interferon preparation should achieve to satisfy commercial requirements. Presently available data suggest that highly purified interferon, in particular, highly purified gamma-interferon, may also be temperature-labile. The problem of temperature-related instability of the lymphokines generally and the interferons in particular is further aggravated by the tendency of these proteinaceous therapeutics to undergo oxidative degradation both during storage and during application. In the case of topical preparations, the tendency toward oxidative degradation is particularly troublesome since it is difficult, if not impossible, to exclude those conditions, e.g., the presence of atmospheric oxygen, which make such degradation possible once the preparation has been applied to the diseased site.
While it might appear to be a simple enough solution to this problem to add an antioxidant to the topical preparation to inhibit or forestall oxidative degradation of the active therapeutic component therein, in practice this is not an acceptable approach with many known antioxidant agents which tend to be somewhat toxic (even if only mildly so) and, being of relatively low molecular weight, are readily absorbed through the skin. (For various types of antioxidants which are commercially available, reference may be made to Kirk-Othmer, The Encyclopedia of Chemical Technology, 3rd Ed., Vol. 2, pp. 132-141.) Even aside from the problem of toxicity, it is generally undesirable to treat with a drug composition containing any bio-active component which is not absolutely essential to achieve the desired therapeutic effect.
Accordingly, the monomeric interferon composition of U.S. Pat. No. 4,432,895 containing a reducing and oxidizing agent, i.e., a redox reagent, such as cysteine and cystine, cysteamine and cystamine, and the like, might not be a likely candidate for a preparation to be applied topically. Indeed, U.S. Pat. No. 4,432,895 makes provision for the removal of the redox reagent from the interferon composition prior to its therapeutic use by known chromatographic procedures or by dialysis.
In view of this state of the art, it is clear that a vehicle for use in topically administering interferon or other drug susceptible to oxidative degradation has a heavy burden to carry in terms of providing a toxicologically acceptable and therapeutically stable preparation.